Parenteral dosage forms with slow drug release properties have been developed to answer the need for improving the therapeutic use of drug substances which should not be administered orally due to their physicochemical properties, and which have a relatively short half life because of which they have to be injected frequently. Frequent injections are uncomfortable to patients, and if the injections have to be given by physicians or nurses, they are also rather costly. The experience of discomfort and pain may result in patient incompliance and jeopardize the success of the therapy.
The number of drug substances which cannot be administered by the convenient oral route is presently increasing, primarily as a consequence of the recent advances of biotechnological research in the pharmaceutical area, which has lead to an increased number of highly potent peptide and protein drugs. Perhaps with the exception of some smaller peptides, however, these compounds are relatively unstable in gastrointestinal fluids and, more importantly, too large and hydrophilic as molecules to become absorbed through the intestinal mucosa to a substantial extent. For some of these drug substances, injectable or implantable controlled release formulations are being developed in order to lower the dosing frequency and thus reduce patient discomfort, and achieve a higher level of compliance and therapeutic success.
Parenteral controlled release dosage forms are usually in the form of macroscopic, solid single- or multiple-unit implants (such as polymeric rods and wafers), microparticle suspensions, and more recently also gels, including in-situ forming gels. Drug-loaded solid implants are available as non-degradable polymeric, ceramic or metal devices which have to be surgically removed after the designated period of drug action, or as biodegradable polymeric forms which require no removal. An example for a non-degradable implant is Bayer's VIADUR®, which releases the peptide drug, leuprolide, over a period of one year. An example for a biodegradable implant is AstraZeneca's ZOLADEX®, which is a polymeric rod capable of releasing the peptide drug, goserelin, over periods of one and three months, respectively.
Shortly after the market introduction of the first biodegradable implants, controlled release microparticles became available, such as Takeda's Lupron® Depot formulations, which release leuprolide over periods of one, three, and four months, respectively. In order to inject such microparticles, they have to be suspended in an aqueous carrier. For stability reasons, however, depot microparticles cannot usually be stored as an aqueous suspension, but they have to be reconstituted from a dry powder.
Various designs of drug-loaded microparticles and methods for their preparation are described in E. Mathiowitz et al., Microencapsulation, in: Encyclopedia of Controlled Drug Delivery (ed. E. Mathiowitz), Vol. 2, pp. 493-546, John Wiley & Sons (1999), which is incorporated herein by reference.
To enable the injection of drug delivery systems through particularly fine needles to provide increased patient comfort, drug delivery scientists have in recent years begun to develop injectable gels which are capable of forming subcutaneous or intramuscular depots. In one of the concepts, gel formulations are designed which are highly shear thinning and thixotropic. By applying shear force prior to administration, the viscosity of these gels is substantially reduced, allowing for injection with a relatively small needle, whereas the gel strength is recovered slowly after administration. According to another concept, liquid compositions are formulated which, after administration, form gels in response to changes of their environment, such as pH, temperature, ionic strength. According to a third approach, liquid polymer formulations comprising a non-aqueous solvent are injected. Upon administration, the solvent diffuses away from the injection site, which leads to the precipitation of polymeric particles or to the formation of a gel.
Biodegradable injectable gels have been discussed in detail by A. Hatefi et al., Journal of Controlled Release (2002) 80:9-28, which document is incorporated herein by reference.
The therapeutic usefulness of several polymeric carriers for controlled release, in particular that of polymers and copolymers of lactic acid and glycolic acid, has been demonstrated for a few active compounds, such as leuprolide, goserelin, buserelin, and triptorelin, which are all peptides with a very large therapeutic index, i.e. having a very low toxicity even at levels far above the therapeutically effective concentrations. In contrast, less tolerable active compounds such as erythropoietins and interferons, whose precisely controlled delivery is necessary for achieving therapeutic effects without intolerable side effects, have not successfully been developed as controlled release dosage forms. A major difficulty is that the biodegradable polymeric carriers used in the successful earlier product are apparently not capable of providing zero-order or nearly zero-order release profiles. Instead, they produce highly undesirable initial burst release upon administration. Furthermore, the autocatalytic degradation of polymers and copolymers of lactic acid and glycolic acid may also lead to dose dumping effects at later stages of drug release. On the other hand, other new polymers which have been discussed as improved controlled release carriers for therapeutic compounds do not have the safety record of the poly(lactides) and poly(glycolides).
Thus, there is a need for new polymeric delivery systems which have proven biocompatibility, but which are also capably of better controlling the release of relatively toxic therapeutic compounds than the previously used carriers.
It is therefore an object of the invention to provide new controlled release compositions comprising one or more polymeric carriers having excellent biocompatibility and a relatively toxic therapeutic compound which should not be given via the oral route, such as a protein.
Another object of the invention is to provide microparticles, implants, and gel compositions comprising an active compound which is released at a controlled rate. Furthermore, it is an object of the invention to provide kits which contain such compositions and pharmaceutical uses thereof. Further objects will become apparent on the basis of the following description and patent claims.